Among metabolic bone diseases are osteoporosis, osteomalacia, osteopenia, bone atrophy, fibrous dysplasia, Paget's disease, hypercalcemia, neoplastic destruction, cancer-related bone resorption, osteolysis, osteoarthritis, and rheumatoid arthritis.
Osteoporosis, the most common metabolic bone disease, occurs as a balance between osteoclastic bone resorption and osteoblastic bone formation is broken and is defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture (The National Institutes of Health (NIH), 2000), indicating that osteoporosis is a kind of systemic diseases which leads to an increase risk of fracture across the body because the bone density is reduced and bone microarchitecture is disrupted. The bone density is homeostatically maintained through the exhaustion of old bones and the formation of new bones. This bone replacement is reduced with age, causing bone loss. Continuous repetition of this imbalance state causes the bone to become thin, increasing the rise of bone fracture and destruction. There are two factors that affect bone density: bone mineral density and bone quality. Bone quality is a composite of properties that make bones resist fracture, such as its microarchitecture, bone turnover, mineral crystal size, accumulated microscopic damage, quality of collagen, etc. Patients with osteoporosis are likely to undergo bone fracture even upon a light impact because their bone calcium level and bone mass, that is, bone density, are significantly reduced. Therefore, patients with osteoporosis are restrained from doing physical activities in daily life.
Osteopenia may be considered to be a precursor to osteoporosis, and is a condition wherein the bone becomes thinner and lighter before development of pores.
Osteomalacia is the softening or bending of the bones caused by a deficiency of vitamin D or excessive loss of calcium, particularly in patients with renal diseases. Bone atrophy is a degenerative decrease in bone mass, that is, a reduction of the bone mass of preexisting bone tissue.
Rheumatoid arthritis is an autoimmune disease that strikes women in their thirties to fifties about four times as often as men. Rheumatoid arthritis typically manifests with signs of symmetrical inflammation around joints such as finger joints, elbow joints, knee joints, etc., with the affected joints becoming swollen, painful and stiff, particularly early in the morning on waking. It is often accompanied by mild fever. Symptoms of rheumatoid arthritis, while disappearing within days to weeks if it is acute, last for months to years, causing deformation and dislocation of joints, and contracture and stiffness of muscles and tendons, thus leading to disability.
Osteoarthritis is a disease which is caused by a local degenerative change in articular cartilage. Osteoarthritis is a chronic degenerative disorder related to aging, affecting 10˜15% of the population. It is estimated that 60˜80% of the population have evidence of osteoarthritis by the age of 65.
In addition, renal osteodystrophy, a bone disease induced by renal failure, adynamic bone disease, which is increasing in prevalence in many chronic kidney disease populations, and infectious bone disease, caused by infection by pyogenic bacteria, are regarded as metabolic bone diseases.
The onset of such metabolic bone diseases is accounted for by an imbalance in activity between osteoblasts and osteoclasts which are responsible for the formation and removal of bone tissues, respectively. Osteoclasts are large cells with multiple nuclei, and function to break up and absorb unnecessary bone tissues during the metabolism of the bone. Mature osteoclasts are multinucleated, originated from hematopoietic stem cells. After differentiation from mesenchymal stem cells, osteoblasts survive for about 34 months. They form new bones at the site where activated osteoclasts break up old bones. A number of osteoblasts produce a matrix of osteoid and mineralize the matrix, accomplishing bone formation. After then, approximately 70% of osteoblasts die while some osteoblasts differentiate into osteocytes and bone lining cells. Since the quantity of bone is maintained by balanced activities of osteoclasts and osteoblasts, it is important to develop a therapeutic agent targeting molecules which exerts significant influence on osteoclastic activity. Given an increased activity, osteoclasts responsible mainly for bone resorption accelerate the degradation of bones, causing osteoporosis characteristics of bone thinning and bone fracture. Therefore, studies have been focused on proteins regulatory of osteoclastic activity as targets for the therapy of bone diseases (Gregory R. Mundy, Journal of Bone and Mineral Metabolism (1996) 14: 59-64; Chad Deal, nature clinical practice RHEUMATOLOGY (2009) vol 5 no 1; Kalervo Vaananen, Advanced Drug Delivery Reviews 57 (2005) 959-971).
Current clinical treatment of metabolic bone diseases resorts mostly to drugs (analgesics, steroidal agents, non-steroidal anti-inflammatory agents), cartilage protectants (hyaluronic acid, glycosamine, chondroitin, etc.), or surgical operation (anthroscopic surgery, wedge high tibial osteotomy, partial arthroplasty, total knee arthroplasty, etc.). However, the drugs non-specifically only relieve pain or inflammation itself, and cartilage protectants perform the protection of the joint simply by providing nutrients for chondrocytes or by absorbing a shock to the joint. Steroids, when used for a long term, induce calcium deficiency, which leads to the onset of osteoporosis, hypertension, and diabetes. Therefore, drugs are applied, for the most part, only for pain relief, and anthroplasty is mainly used for permanent purposes, but neither drugs nor surgical operations have been regarded as fundamental cures for metabolic bone diseases. In recent years, herbal medicaments and nutrients have been suggested as therapeutics for arthritis, but much must be done to demonstrate their therapeutic effects and mechanisms. Anti-inflammatory analgesics, simple symptomatic agents, cause significant side effects after long-term use, in addition to being unable to effectively regulate arthritis. There has been much difficulty in treating patients, especially the elderly.
Because, on the whole, therapeutic drugs for arthritis are required to be administered for a long term, there is a need for the development of a drug with fewer side effects.